I. What every physician needs to know.

Non-Hodgkin’s lymphomas (NHL) result from a malignant proliferation of lymphoid cells. Most, but not all, are of B-cell origin, with a smaller group derived from T-cells or natural killer cells. From a prognostic and therapeutic standpoint, they can be grouped into indolent subtypes (including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma and the marginal-zone lymphomas) and aggressive subtypes (including diffuse large B-cell lymphoma and mantle cell lymphoma) and highly aggressive subtypes (including Burkitt lymphoma, lymphoblastic lymphoma and AIDS-related lymphomas). The indolent subtypes progress slowly and may not require therapy for many years, but they are incurable. The aggressive and highly aggressive subtypes progress rapidly and require urgent intervention, but are potentially curable.

Definitive diagnosis requires lymph node biopsy. Because the precise architecture of the affected lymph nodes impacts the diagnosis, excisional biopsy – usually of the largest lymph node – is necessary. Core biopsies may be needed for deep lymph nodes. The biopsy specimen then undergoes cytologic, histopathologic, fluorescence in situ hybridization, immunophenotypic analysis and gene expression analysis.

A. History Part I: Pattern Recognition:

Patients are often asymptomatic and the diagnosis is entertained because of the presence of lymphadenopathy. The nodes are typically firm, rubbery and not tender. They can wax and wane in size, leading the clinician to suspect an infectious etiology. The liver and spleen may be enlarged. Some patients – about 1/3 of those with aggressive lymphomas – present with fevers, night sweats and loss of more than 10% of their body weight within the prior 6 months. These so-called B symptoms portend a worse prognosis.

B. History Part 2: Prevalence:

The incidence is increasing, particularly for aggressive lymphomas. It is estimated that more than 65,000 new cases were diagnosed and over 20,000 deaths occurred from NHL in 2010. Each year there are 19 new cases to 100,000 persons in the US; the incidence in people over 65 is 68/100,000. Median age at diagnosis is 66. Children and adults of any ethnic group and age can be affected, although NHL is rare in infants.

Patients at increased risk include those with immunodeficiency states such as HIV/AIDS, those under immunosuppressive treatment for solid organ transplants, and patients with inherited immune deficiencies such as Wiskott-Adlrich. Particularly in immunodeficient patients there is a predilection for Epstein-Barr virus (EBV) associated lymphoma (e.g., Burkill lymphoma).

C. History Part 3: Competing diagnoses that can mimic B-cell non Hodgkin's lymphoma

Many disorders can cause lymphadenopathy and B symptoms, including other malignancies and a multitude of infectious diseases.

D. Physical Examination Findings.

Enlarged, firm, non-tender rubbery lymph nodes can be present in any lymphatic chain and in node-bearing areas such as Waldeyer’s ring. Splenomegaly and hepatomegaly may be present. Extranodal involvement can develop in about half of patients with NHL, and examination should focus on the GI tract, skin, testes (solitary mass), bones (focal pain) and nervous system (focal lesions or mental status changes on exam).

E. What diagnostic tests should be performed?

Excisional biopsy of the largest palpable lymph node should be carried out if at all possible. If the lymph nodes are deep seated, a core needle biopsy may be required, but this may not yield a definitive diagnosis. Fine-needle aspiration should play no role in the diagnosis of NHL.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The lymph node biopsy specimen should be sent for histopathologic, cytogenetic and immunophenotypic analysis plus gene expression profiling. Other testing should include a CBC and platelet count (looking for cytopenias related to splenic enlargement and bone marrow involvement), a chemistry panel including liver function tests and renal function tests, electrolytes and a uric acid (the last two screening for tumor lysis syndrome), and an LDH and beta-2 microglobulin for prognosis. A bone marrow aspirate and biopsy are needed for staging. Evaluation of the CSF is needed for those lymphomas with a high predilection for CNS involvement; these include the highly aggressive subtypes, primary CNS lymphoma and cases of diffuse large B-cell lymphomas that involve the epidural, paraspinal, testicular, bone marrow and paranasal tissues. An acute hepatitis panel (particularly looking for types B and C) and HIV testing should be performed, as these will impact treatment modalities. Esophagogastroduodenoscopy and colonoscopy should be performed in patients with mantle cell lymphoma and in other select cases.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CT scans of the chest, abdomen and pelvis are required for staging. PET scanning may also be useful, and MRI of the brain is usually done when CNS involvement is suspected.

Prior to the use of some chemotherapeutic agents, an echocardiogram or multigated acquisition assessment (MUGA) of baseline heart function is required.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

N/A

III. Default Management.

Management involves a multidisciplinary team. Once the diagnosis is made, a staging workup is performed as above prior to initiating treatment. The decision to treat the patient as an inpatient or outpatient depends on how sick the patient is and the subtype of lymphoma. Treatment for most patients with NHL is delivered in an outpatient setting. Bulky tumors and aggressive subtypes are often treated in the hospital. For highly aggressive lymphomas, transfer to a center experienced in treating these lymphomas is generally recommended.

The uric acid potassium, phosphate, calcium and creatinine should be monitored daily.

Rituximab can cause reactivation of hepatitis B, so liver tests should be monitored.

Bone marrow suppression usually nadirs 1-2 weeks after treatment is started, so the CBC should be monitored during this time.

Neutropenic fever should be treated accordingly.

D. Long-term management.

Chemotherapy for aggressive and highly aggressive NHL is most often administered in 3 week cycles.

E. Common Pitfalls and Side-Effects of Management

The chemotherapeutic regimens for NHL will inevitably cause cytopenias, with nadirs occurring in 1-2 weeks. In addition, many agents in common use are metabolized by the cytochrome p450 system, so the half-life of many medications (e.g., phenytoin, cimetidine and erythromycin) may be altered.

Tumor lysis syndrome is heralded by the development of hypocalcemia, hyperkalemia, hyperphosphatemia and hyperuricemia, as well as acute renal failure; consult nephrology at once because the treatment for this is hemodialysis.

Doxorubicin is a vesicant that can cause necrosis upon extravasation.

A. Renal Insufficiency.

For patients with renal insufficiency, dosage adjustments of the chemotherapeutic regimen will be required. Issues with fluid balance may also make tumor lysis syndrome an important consideration, in which case rasburicase is typically preferred over allopurinol.

B. Liver Insufficiency.

Dosage adjustments will be required.

C. Systolic and Diastolic Heart Failure

Consider alternative chemotherapeutic regimens. Patients may also be at risk for developing other heart conditions during therapy. Digoxin interacts with some chemotherapeutic agents.

D. Coronary Artery Disease or Peripheral Vascular Disease

Because thrombocytopenia can result from therapy, the use of antiplatelet and anticoagulant drugs may increase the risk of bleeding complications.

E. Diabetes or other Endocrine issues

Corticosteroids, a component of many chemotherapeutic regimens, can cause diabetes to evolve or existing diabetes to become poorly controlled.

F. Malignancy

Treatment can lead to secondary malignancies, including acute myelogenous leukemia and myelodysplastic syndrome.

G. Immunosuppression (HIV, chronic steroids, etc).

HIV patients should be on effective antiretroviral therapy. In all patients on chemotherapy, neutropenia can lead to life-threatening infections even without significant symptomatology.

H. Primary Lung Disease (COPD, Asthma, ILD)

Patients with underlying lung disease may be more prone to respiratory pathogens. Those with asthma or chronic lung disease may already be on steroids, so it is important to reconcile treatments if the chemotherapeutic regimen contains a corticosteroid.

I. Gastrointestinal or Nutrition Issues

Nausea, vomiting and diarrhea are common. Antiemetics should be prescribed as needed or on a regular schedule.

J. Hematologic or Coagulation Issues

Thrombocytopenia and anemia are common at nadir. Cyclophosphamide may potentiate the anticoagulant effects of warfarin.

K. Dementia or Psychiatric Illness/Treatment

Chemotherapy and radiation therapy require frequent scheduled follow-up and close surveillance. The practitioner must evaluate the patient’s ability to comply often in conjunction with caregivers, prior to embarking on a treatment plan. Strong social support is often needed.

A. Sign-out considerations While Hospitalized.

With rituximab, alert the covering practitioner that infusion reactions such as fever, chills, headache, bronchospasm, dyspnea and hypotension may improve with slowing or interrupting the infusion.

With rituximab, alert the covering practitioner that infusion reactions such as fever, chills, headache, bronchospasm, dyspnea and hypotension may improve with slowing or interrupting the infusion.

Doxorubicin may cause an orange discoloration of the urine.

If the central line does not demonstrate adequate return, consider a patency study prior to infusion of doxorubicin, a vesicant.

B. Anticipated Length of Stay.

Patients can usually be discharged after completion of their chemotherapeutic regimen, which typically lasts ~5 days. Otherwise, NHL therapy is usually started on an outpatient basis.

C. When is the Patient Ready for Discharge.

Patients can usually be discharged upon diagnosis of an indolent lymphoma or after completion of their first round of therapy for highly aggressive lymphoma if there is no evidence of tumor lysis syndrome.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

For patients with indolent NHL, an appointment should be made to see an oncologist after the staging workup is completed. Those with aggressive NHL who have not yet been treated should see an oncologist within days.

Patients who have started therapy should have their labs monitored, beginning before the expected nadir, and should see their oncologist prior to the next scheduled cycle of therapy (within two weeks).

Patients with HIV should also be seen by an infectious disease specialist.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

If evaluation by an oncologist will be done as an outpatient prior to initiating therapy, a good baseline staging workup includes a CT of the chest, abdomen and pelvis, CBC and CMP.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

A CBC, BMP and LFT’s should be done on the day of the clinic visit. A CBC should be done 1-2 times per week during the expected nadir for patients who have received chemotherapy. Patients should be instructed to check their temperature regularly and call at once if fever develops.

E. Placement Considerations.

Line care is required for patients with indwelling lines; the specific regimen depends on the type of line and institutional protocols.

F. Prognosis and Patient Counseling.

Indolent lymphomas, while not curable, have a median survival of 10 years. Because they are recurrent processes, the goals of treatment include prolonging disease-free survival, maintaining quality of life, and providing long-term support.

Aggressive lymphomas can be cured in 30-60% of patients with intensive chemotherapy. Overall 5 year survival is 50-60%. Most relapses occur in the first two years of therapy. The treatment goal is cure, along with managing the side effects and long-term toxicities of therapy.

A patient’s prognosis depends most prominently on the histologic subtype. In addition, the prognosis is worse for patients over the age of 60 or with poor performance status, with bulky disease, and/or with the presence of B symptoms.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Prophylaxis against the development of a deep vein thrombosis with low molecular weight heparin is recommended, but decisions about using anticoagulant therapy will be impacted by underlying cytopenias.

Tumor lysis prophylaxis should be instituted as discussed above.

Many chemotherapeutic regimens include prophylaxis against viral, fungal and some bacterial agents.

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